Patch Testing Increases the Likelihood of Recognizing

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64
autoimmune diseases.2 The course of this disease is selflimiting. The lesions resolve within 2 to 4 weeks without
residual scarring or recurrence.1
Although its etiology is unknown, the development of
this disease is associated with various viral infections,
the most common of which is Epstein-Barr virus.1,3-9 The
case reported here involved acute ulceration of the vulva
(Lipschütz ulcers), associated with primary influenza A
virus infection. Because of the high incidence of infection
by this virus and the great public alarm regarding the H1N1
serotype, we believe that it is important to study acute
ulceration of the vulva and its relationship with influenza
A virus infection.10
References
1. Farhi D, Wendling J, Molinari E, Raynal J, Carcelain G, Morand
P, et al. Non-sexually related acute genital ulcers in 13 pubertal
girls: a clinical and microbiological study. Arch Dermatol.
2009;145:38–45.
2. Fett N, Hinshaw M. Multiple painful vaginal ulcerations. Arch
Dermatol. 2008;144:547–52.
3. Martín JM, Molina I, Ramón D, Alpera R, de Frutos E, García L,
et al. Úlceras vulvares agudas de Lipschütz. Actas Dermosiiliogr.
2004;95:224–6.
4. Halvorsen JA, Brevig T, Aas T, Skar AG, Slevolden EM, Moi H.
Genital ulcers as initial manifestation of Epstein-Barr virus
infection: two new cases and a review of the literature. Acta
Derm Venereol. 2006;86:439–42.
CASE AND RESEARCH LETTERS
5. Barnes CJ, Alio AB, Cunningham BB, Friedlander SF. EpsteinBarr virus associated genital ulcers: an under-recognized
disorder. Pediatr Dermatol. 2007;24:130–4.
6. Crawford DH, Swerdlow AJ, Higgins C, McAulay K, Harrison N,
William H, et al. Sexual history and Epstein-Barr virus infection.
J Infect Dis. 2002;186:731–6.
7. Portnoy J, Ahronheim GA, Ghibu F, Clecner B, Joncas JH.
Recovery of Epstein-Barr virus from genital ulcers. N Engl J
Med. 1984;311:966–8.
8. Cheng SX, Chapman MS, Margesson LJ, Birenbaum D. Genital
ulcers caused by Epstein-Barr virus. J Am Acad Dermatol.
2004;51:824–6.
9. Navarro Ll, Domenech V, Elizalde J, Pujol E. Primoinfección por
el virus de Epstein-Barr: una causa poco conocida de úlcera
genital aguda. ¿Úcera de Lipschütz? Rev Clin Esp. 1996;196:570–
1.
10. Wetter DA, Bruce AJ, MacLaughlin KL, Rogers III RS. Ulcus
vulvae acutum in a 13-year-old girl after inluenza A infection.
Skinmed. 2008;7:95–8.
A. Esteve-Martínez,* J. López-Davia, A. García-Rabasco,
I. Febrer-Bosch, V. Alegre-de Miquel
Servicio de Dermat ología, Consorcio Hospit al General
Universit ario de Valencia, Valencia, Spain
*Corresponding author.
E-mail address: alteamarsa@hotmail.com (A. EsteveMartínez).
Patch Testing Increases the Likelihood of
Recognizing Lamotrigine as a Cause
of Drug-Induced Rash
La imputabilidad de la lamotrigina
en el exantema medicamentoso aumenta
con las pruebas epicutáneas
To t he Edit or:
Lamotrigine, an aromatic antiepileptic drug, is mainly used
to manage epilepsy and bipolar disorder and to stabilize
mood. The most common adverse reaction to this drug is
a skin rash that typically develops in the first 8 weeks of
treatment.
The patient was a 64-year-old woman with a history of
depression. She had been on treatment with ranitidine and
venlafaxine for more than 2 years, and was also receiving
lamotrigine. She attended the emergency department with a
4-day history of pruritic, erythematous macules and papules that
showed cephalocaudal progression (Figures 1 and 2), discomfort
in the mouth, and fever of 38ºC. She had been prescribed
lamotrigine 12 days before the symptoms commenced.
A lamotrigine-induced drug rash was suspected. Treatment
was therefore withdrawn and the patient was prescribed
Figure 1
Skin symptoms.
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CASE AND RESEARCH LETTERS
Figure 2
65
Skin symptoms.
Figure 3
prednisone, 0.5 mg/kg/d, and dexchlorpheniramine,
6 mg/8 h. Biopsy was performed in the outpatient clinic
6 days after the onset of the skin rash, and the result was
compatible with toxicoderma. The lesions resolved 12
days after starting treatment with the corticosteroids and
antihistamines.
With a diagnosis of a probable lamotrigine-induced drug
reaction, the patient was referred for patch testing, which
was performed 5.5 months after the episode resolved.
Patches were placed on the upper part of the patient’s
back and left for 48 hours. The standard GEIDAC (Spanish
Contact Dermatitis Research Group) battery of tests was
used: Thin-Layer Rapid Use Epicutaneous Test (Mekos
Laboratorios ApS, Denmark) and additional allergens
(Chemotechnique Diagnostics, Sweden). The commercial
form of lamotrigine tablets (Lamotrigina Merck) was also
tested by crushing the tablets and preparing 30% dilutions
in water and petroleum jelly.
Readings were made at 72 and 168 hours (Figure 3), in
accordance with the guidelines of the International Contact
Dermatitis Research Group. Positive results were observed
for Lamotrigina Merck in water (++) and in petroleum
jelly (+) on day 3 and day 6; results were also positive for
nickel (++) and palladium (+), but these results were not
considered relevant. The patch test results considerably
raised the probability that lamotrigine was the cause of the
drug reaction in our patient.
Lamotrigine-induced drug reactions are generally mild
and resolve spontaneously; however, reactions should
be monitored closely as they can be life-threatening.
Patients are informed that one of the undesirable side
Table 1
Patch test results.
effects is the possible development of Stevens-Johnson
syndrome.1
We frequently encounter skin reactions of this kind in
routine clinical practice. It is often difficult to establish the
cause, especially in patients receiving multiple treatments.2
Diagnosis must be based on clinical and chronological
parameters as there is no standard laboratory test that can
determine the origin of this type of reaction.
Experts are of the opinion that patch testing of medical
products should be performed 2 to 6 months after a reaction.
When the commercial form of a drug is used, it should be
crushed and prepared in water and in petroleum jelly at a
concentration of 30%. Readings should be made at 48 and
96 hours, and if results are negative, again at 7 days.3
We have found only 3 previous articles referring to
the use of this type of test in patients with a suspected
lamotrigine-induced allergic drug reaction (Table 1).
The significance of patch testing in drug-induced reactions
is variable, with positive reactions reported in 10% to 50%
of cases, depending on the study4,7; however, it is not yet
possible to accurately determine the specificity of the test
or its negative or positive predictive values. The rate of
positive results is affected both by the drug and by the
type of clinical reaction. Higher yields are obtained when
the following lesions are present: maculopapular rash,5
drug-induced eruption,4,6,8,9 disseminated eczema, systemic
contact dermatitis, baboon syndrome (intertriginous drug
eruption), and drug reactions with eosinophilia and systemic
symptoms (DRESS). Very low yields are obtained in cases
Patch test results in the studies reviewed
Lamminiausta K
Monzón S5
Hesiao CJ6
4
Patients
Controls
P+
C+
Concentration
5
1
1
5
5
0
0
1
1
0
0
0
30% water and petroleum jelly
10% water and petroleum jelly
50% water and petroleum jelly
C+: positive results for controls; P+: positive results for patients.
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66
with urticaria, Stevens-Johnson syndrome, toxic epidermal
necrolysis, pruritus, or vasculitis.10
Patch testing with drugs has been demonstrated to
be useful in determining the cause of drug-related skin
reactions.9,11 The main advantages of patch testing over
other diagnostic procedures are that serious adverse
reactions are rare and testing can be performed with any
commercial form of the drug.
Given the absence of a gold standard for determining
the causal agent and the importance of reaching a specific
diagnosis in these patients, other tests, such as prick,
intradermal, and oral challenge tests, should be performed
if the results of the patch tests are negative.
Conlict of Interest
The authors declare they have no conflict of interest.
References
1. Francesco G, Cristiana A, Rocco LV, Marinella V, Maurizio E, Antonino
R. Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant
Drugs: A Review. Curr Pharm Des. 2008;14:2874–82.
2. Ghislain PD, Bodarwe AD, Vanderdonckt O, Tennstedt D, Marot
L, Lachapelle JM. Drug-induced eosinophilia and multisystemic
failure with positive patch-test reaction to spironolactone:
DRESS syndrome. Acta Derm Venereol. 2004;84:65–8.
3. Barbaud A, Gonc¸alo M, Bruynzeel D, Bircher A. Guidelines for
performing skin tests with drugs in the investigation of
cutaneous adverse drug reactions. Contact Dermatitis.
2001;45:321–8.
Pregnancy-Related Erythema Annulare
Centrifugum
Eritema anular centrífugo asociado
a gestación
To t he Edit or:
Erythema annulare centrifugum (EAC) is an uncommon skin
disease consisting of annular and polycyclic, erythematous,
papular lesions with borders that advance slowly but do
not leave scars. Although its etiology remains unknown,
the disease has been associated with a range of clinical
conditions, including pregnancy.1-3 We describe a new case
of EAC associated with pregnancy, provide a review of the
relevant literature, and discuss the role of hormones as a
possible trigger.
A 34-year-old woman in her 28th week of pregnancy
and with a history of allergy to tetracyclines consulted for
slightly pruritic, annular lesions on the trunk and limbs
which had appeared in the 12th week of pregnancy. She
said she had not had any recent infections or been exposed
CASE AND RESEARCH LETTERS
4. Lamminiausta K, Kortekangas-Savolainen O. The usefulness of
skin tests to prove drug hypersensitivity. Br J Dermatol.
2005;152:968–74.
5. Monzón S, Garces MM, Reiehell C, Lezaun A, Colás C. Positive
patch test in hypersensitivity to lamotrigine. Contact
Dermatitis. 2002;47:361.
6. Hesiao CJ, Lee JY, Wong TW, Sheu HM. Extensive ixed drug
eruption due to lamotrigine. Br J Dermatol. 2001;144:1289–
91.
7. Barbaud A. Drug patch testing in systemic cutaneous drug
allergy. Toxicology. 2005;209:209–16.
8. Alanko K, Stubb S, Reitamo S. Topical provocation of ixed drug
eruption. Br J Dermatol. 1987;116:517–61.
9. Alanko K. Topical provocation of ixed drug eruption. A study of
30 patients. Contact Dermatitis. 1994;31:25–7.
10. Puig L, Nadal C, Fernández-Figueras MT, Alomar A.
Carbamazepine-induced drug rashes; diagnostic value of patch
test depends on clinico-pathologic presentation. Contact
Dermatitis. 1996;34:435–7.
11. Elzagallaai AA, Knowles SR, Rieder MJ, Bend JR, Shear NH,
Koren G. Patch Testing for the Diagnosis of Anticonvulsant
Hypersensitivity Syndrome. A Systematic Review. Drug Saf.
2009;32:391–408.
L. Fuertes,* I. García-Cano, J. Ortiz de Frutos,
F. Vanaclocha
Servicio de Dermat ología, Hospit al 12 Oct ubre,
Madrid, Spain
*Corresponding author.
E-mail address: laurafdv@hotmail.es (L. Fuertes).
to any medications, except for folic acid, which she had
been taking since early pregnancy.
Physical examination revealed annular erythematous
lesions of various sizes, with slightly raised borders, a
clear center, without vesiculation, and scaling on the
inner margins of the rims; the lesions were located
on the thighs, the trunk, and the arms (Figure 1). We
requested a biopsy from the advancing border of a lesion
to corroborate an initial diagnosis of EAC. Histologically,
there was a lymphohistiocytic infiltrate around the
superficial vessels with areas of spongiosis and focal
parakeratosis. Periodic acid-Schiff staining for fungi was
negative (Figure 2). Blood, urine, and serology studies
for toxoplasmosis, syphilis, measles, hepatitis B and
C, and human immunodeficiency virus were normal.
Following confirmation of the suspected diagnosis of
EAC, treatment was initiated with methylprednisolone
0.1% cream applied twice daily. However, the lesions did
not improve and several new lesions appeared over the
course of the pregnancy. Within a few hours of delivery,
the lesions started to regress rapidly and had disappeared
almost completely 3 days later (Figure 3). Five days
after delivery, coinciding with the onset of lactation, the